Patient with TNBC IIIA with left breast multicentric compromise, who, after receiving standard neoadjuvant treatment, followed by surgery, radiotherapy, and adjuvant capecitabine, presents cervical lymph node recurrence after a 10-mo disease-free interval. After surgery, she participated in 2 biomarker research studies, detecting the presence of a positive PIK3CA mutation in tumor tissue and peripheral blood (liquid biopsy).
The PI3K/AKT/mTOR pathway is an oncogenic intracellular pathway that regulates cell proliferation, metabolism, growth, survival, and apoptosis. The PIK3CA mutation, being the most common of the PI3K/AKT signaling pathway amplifications, is present in all molecular subtypes of breast cancer, and is detected in 20%-25% of all cases. Although these individual mutations are rare, the combined activated mutations in PIK3CA and AKT1, with inactivating mutations in PTEN (a tumor suppressor gene that is inactivated when mutations are detected), occur in 25%-30% of metastatic TNBC (mTNBC). It has been determined that the PIK3CA mutation has an independent negative prognostic value of survival, as a systematic review has shown that patients with breast cancer and high levels of ctDNA after receiving neoadjuvant treatment have early disease relapse[9-11].
Liquid biopsy is being evaluated in breast cancer as a potential tool to capture tumor evolution in real time, to guide and monitor systemic treatment, as well as being a promising method to identify drug resistance mechanisms through the detection of genomic alterations[9,10]. ctDNA corresponds to a small fraction (0.01%-10%) of short cell-free DNA fragments from tumors and are detectable in body fluids (for example: Blood, saliva, or urine). In TNBC, there is evidence that evaluation of mutated PIK3CA in circulating tumor DNA (ctDNA) using liquid biopsy has a potential prognostic value as a biomarker, including diagnosis and follow-up during treatment (response to NAT)[12,13]. Furthermore, in the early disease scenario (with curative intention), its value for monitoring during treatment has been demonstrated, as well as for detecting relapse and early metastasis, as happened in our patient[12,13]. Some trials have demonstrated the potential of ctDNA in peripheral blood (both early and metastatic disease) for diagnosis, treatment, and prognosis. There are currently no guidelines or regulatory approvals to monitor response in breast cancer patients.
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Novel trials has shown that ctDNA has a prognostic value in TNBC, predicting minimal residual disease (MRD) and early relapse after neoadjuvant chemotherapy with curative intent with high specificity[16,17]. ctDNA detection is useful for monitoring micrometastases or MRD after neoadjuvant chemotherapy and surgery with apparent curative intent in patients with early breast cancer either at a single point (post-surgery) or with serial plasma samples (during follow-up). Consistently, post-surgical levels of ctDNA were found to be predictive of poor prognosis and risk of relapse[16,17]. In one trial, detection of PIK3CA mutation using post-surgical ctDNA predicted disease relapse after 8.1 mo of follow-up. Another trial demonstrated the ability of ctDNA to identify patients at risk of relapse [23/26 patients who relapsed (88.4%) had a history of ctDNA detection with a median time of 10.7 mo before clinical relapse]. These results regarding time to early relapse are very similar with our patient. Moreover, the BRE 12-158, a phase II trial presented at the San Antonio Breast Cancer Symposium 2019, showed that the presence of frequent mutations in breast cancer detected by ctDNA and circulating tumor cells are useful to predict recurrence after neoadjuvant chemotherapy in patients with early TNBC. ctDNA was detected in 64% of samples, and TP53 was the most frequent gene. ctDNA was associated with poor distant disease-free survival (DDFS): after 24 mo, the likelihood of DDFS was 25% worse in patients with positive ctDNA (56%) vs those with negative ctDNA (81%) (hazard ratio [HR]: 2.99, 95% confidence interval [CI]: 1.38-6.48, P = 0.0055). Women with positive ctDNA have 3 times the risk of developing distant disease recurrence compared to those with negative ctDNA (disease-free survival: HR: 2.67, 95%CI: 1.28-5.57, P = 0.0069). Furthermore, ctDNA-positive women had a 4.1-fold higher risk of death compared to ctDNA-negative women (overall survival: HR: 4.16, 95%CI: 1.66-10.42, P = 0.0024).
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Although there is a positive PIK3CA mutation result in this case report, to date, there are no standardized procedures for PIK3CA detection in breast cancer in Peru. Therefore, the application of ctDNA should be based on defined protocols to ensure reproducibility of results, due to mostly undetectable levels of ctDNA in early breast cancer. Finally, it is not known whether the presence of the PIK3CA mutation in peripheral blood and tumor tissue confers a worse prognosis compared to having the mutation in 1 of the 2 samples evaluated (blood, tissue). These findings could increase the interval of control visits or earlier approaches for follow-up to detect local or distant relapse.